The ability of the mammalian immune system to recognize “self” versus “non-self” antigens is vital to successful host defense against invading microorganisms. “Self” antigens are those which are not detectably different from an animal's own constituents, whereas “non-self” antigens are those which are detectably different from or foreign to the mammal's constituents. A normal mammalian immune system functions to recognize “non-self antigens” and attack and destroy them. An autoimmune disorder such as for example, rheumatoid arthritis, insulin-independent diabetes mellitus, acquired immune deficiency syndrome (AIDS), multiple sclerosis, and the like, results when the immune system identifies “self” antigens as “non-self”, thereby initiating an immune response against the mammal's own body components (i.e., organs and/or tissues). This creates damage to the mammal's organs and/or tissues and can result in serious illness or death.
Predisposition of a mammal to an autoimmune disease is largely genetic; however, exogenous factors such as viruses, bacteria, or chemical agents may also play a role. Autoimmunity can also surface in tissues that are not normally exposed to lymphocytes such as for example, neural tissue and the eye (particularly the lens or the cornea). When a tissue not normally exposed to lymphocytes becomes exposed to these cells, the lymphocytes may recognize the surface antigens of these tissues as “non-self” and an immune response may ensue. Autoimmunity may also develop as a result of the introduction into the animal of antigens which are sensitive to the host's self antigens. An antigen which is similar to or cross-reactive with an antigen in an mammal's own tissue may cause lymphocytes to recognize and destroy both “self” and “non-self” antigens.
It has been suggested that the pathogenesis of autoimmune diseases is associated with a disruption in synthesis of interferons and other cytokines often induced by interferons (Skurkovich et al., Nature 217: 551–552, 1974; Skurkovich et al., Annals of Allergy, 35:356, 1975; Skurkovich et al., J. Interferon Res. 12, Suppl. 1: S 110, 1992; Skurkovich et al., Med. Hypoth., 41:177–185, 1993; Skurkovich et al., Med. Hypoth., 42:27–35, 1994; Gringeri et al., Cell. Mol. Biol. 41(3):381–387, 1995; Gringeri et al., J. Acquir. Immun. Defic. Syndr., 13:55–67, 1996). In particular, interferon (IFN) gamma plays a significant pathogenic role in autoimmune dysfunction. IFN gamma stimulates cells to produce elevated levels of HLA class II antigens (Feldman et al., 1987, “Interferons and Autoimmunity”, In: IFN γ, p. 75, Academic Press). It is known that IFN gamma participates in the production of tumor necrosis factor (TNF), and it is also known that TNF also plays a role in stimulation of production of autoantibodies. In view of this, therapies to modulate these cytokines have been developed. Clinical success in treating several autoimmune diseases using antibodies to IFN gamma has been reported (Skurkovich et al., U.S. Pat. No. 5,888,511).
However, while an autoimmune response is considered to be typical in diseases such as multiple sclerosis and rheumatoid arthritis, one area of medicine where treatment of autoimmune or hyperimmune responses has not been fully explored is the area of transplant therapy. Autoimmunity arising from transplant rejection is typical in transplant patients. Rejection of a transplant is the organism's normal reaction to invading foreign antigens. In particular, transplantation of tissues or organs such as the eye, which is not normally exposed to lymphocytes, skin, heart, kidney, liver, bone marrow, and other organs, have a high rate of rejection, which rejection is largely the result of a hyperimmune reaction.
Hyperimmune reactions including rejection of tissue transplants in the eye are of considerable concern. Corneal transplants, lens replacements, and the like, are frequently rejected when transplanted into a human patient. In addition, other diseases in the eye, such as for example, keratoconjunctivitis sicca (dry eye syndrome), episcleritis, scleritis, Mooren's ulcer, ocular cicatricial pemphigoid, orbital pseudotumor, iritis, central serous retinopathy, Graves' ophthalmopathy, chorioretinitis, Sjogren's syndrome, uveitis, and Stevens-Johnson syndrome may also be the result of a hyperimmune reaction in the eye. Systemic infections, such as tuberculosis, syphilis, AIDS, toxoplasmosis infection, and cytomegalovirus retinitis, may also cause eye diseases, including but not limited to, uveitis, enophthalmitis, retinitis, choroiditis, and retinal necrosis. These types of hyperimmune reactions typically result in blurred vision and eventually blindness. Current therapies to treat such hyperimmune responses include corticosteroid treatment, including dexamethasone, and treatment with an anti-inflammatory preparation. To date, there are no successful or long-term methods or compositions for effectively treating hyperimmune reactions in the mammalian eye and other organs.
Of the above-mentioned hyperimmune responses in the eye, uveitis poses a significant threat to the eyesight of an afflicted patient. Uveitis is a general condition describing the inflammation of all or a portion of the uvea, the continuous layer of fibrous tissue that surrounds the eye. The uvea comprises the iris, the ciliary body, and the choroid. The iris is the circular, colored portion of the eye, the ciliary body is a thick ring of tissue that helps control the shape of the lens and is connected to both the iris and to the front portion of the choroid. The choroid is a membrane full of blood vessels that surrounds the eye. It extends from the ciliary body to the connection of the optic nerve with the back of the eye. Anterior uveitis (iritis) affects the front portion of the eye, intermediate uveitis (cyclitis) affects the ciliary body, and posterior uveitis (choroiditis) affects the back portion of the uvea. Diffuse uveitis affects all portions of the uvea.
Anterior uveitis commonly occurs in conjunction with juvenile rheumatoid arthritis, but does not manifest in all juvenile arthritis patients. Uveitis is most likely to be present in juvenile arthritis patients with pauciarticular disease (fewer than five joints involved), a positive anti-nuclear antibody test, and a negative rheumatoid factor test.
Although uveitis is a documented autoimmune disease, the mechanism leading to inflammation of the uvea is unknown. Uveitis is a secondary manifestation of many autoimmune and infectious diseases, such as ankylosing spondylitis, juvenile rheumatoid arthritis, sarcoidosis, toxoplasmosis, herpes, syphilis, and cytomegalovirus infection. However, the etiology is not known in from about 33% to about 50% of uveitis cases. No known racial predilection for uveitis exists, but in juveniles, the disease appears in girls approximately four times more often than boys.
The symptoms of uveitis can vary depending on the location of the uveitis; acute and severe symptoms are generally more common in anterior uveitis and can include: eye pain, eye redness, photophobia, blurred or decreased vision and blindness. Other symptoms include “floaters” which are small specks or clouds that move with the field of vision, chronic flare in the eye, band keratopathy, secondary glaucoma and posterior subcapsular cataracts.
The morbidity and mortality of uveitis are often related to two extremes of treatment, either lack thereof or overzealous treatment. Mortality more often results from the latter. Standard treatments include both medical and surgical treatments. Surgical intervention is reserved for chelating treatment in addressing the problems associated with band keratopathy and cataract or glaucoma surgery, if the disease should progress to such a point. Medical intervention is the most common method of addressing the initial symptoms of uveitis and resulting sequelae. Medical treatments are divided into four major categories, and are used depending on the state of the disease, the patient's overall health and age, and other factors well known to one of ordinary skill in the art.
Topical corticosteroids are the primary form of medical treatment for uveitis. Prednisone is often the first line drug administered to a patient afflicted with uveitis, but may result in increased intraocular pressure or cataracts with long-term use, as well as the immunosuppression and other side effects common to corticosteroids. Triamcinolone acetonide is often administered as a periocular injection for more severe cases of uveitis, but infections, edema, osteoporosis, psychosis and growth suppression are often noted as side effects of this particular treatment.
Treatment of uveitis can also consist of corticosteroid administration in conjunction with chronic dilation until the inflammation is resolved. Corticosteroid therapy may be topical (eye-drops), injected adjacent to the eye, or even oral in uveitis cases refractory to topical or injected steroids.
Cycloplegics are used to block nerve impulses to the pupillary sphincter and ciliary muscles, which serve to ease the pain and photophobia of uveitis. Cyclopentolate and homatropine hydrobromide are both commonly used cycloplegics, but carry the risk of increased intraocular pressure as well as systemic toxic anticholinergic effects.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of uveitis to reduce pain and inflammation. While they often do not exhibit the risks and side effects of the above mentioned drugs, chronic and regular use of NSAIDs is required to manage the inflammation of uveitis, and they are not as effective as corticosteroids.
Finally, severe cases of uveitis are sometimes treated with systemic immunosuppressive drugs, often as a second line drug in conjunction with corticosteroids. Methotrexate, cyclosporine A, cyclophosphamide and chlorambucil are the most commonly used immunosuppressive drugs in the treatment of uveitis. The major drawbacks when using these drugs range from renal and liver failure, anemia and chromosome damage to susceptibility to bacterial, viral and fungal infections.
There exists a long felt need to develop safe and effective therapies for treating hyperimmune responses of the eye, especially hyperimmune responses such as uveitis. The present invention meets this need.